Corticotropin releasing factor (CRF) is a peptide comprised of 41 amino acids. Vale et al. Science (1981) 213:1394. It is secreted by the hypothalamus, serving to coordinate the neuroendocrine response to stress by the hypothalamic-pituitary-adrenal (HPA) axis. Dunn et al. Brain Res. Rev. (1990) 15:71. As well as its role at the pituitary gland, CRF has demonstrated broad extrahypothalamic distribution in the central nervous system, producing a wide variety of autonomic, electrophysiological, and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain. Vale et al. Rec. Prog. Horm. Res. (1981) 39:245; Koob et al. Persp. Behav. Med. (1985) 2:39. De Souza (1985) 5:3189. CRF has been implicated in the pathophysiology of depression and other affective disorders which, in turn, has led to research of CRF1 antagonists. Arborelius et al. J. Endocrinol. (1999) 160:1; Kasckow et al. Peptides (2001) 22:845; Nemeroff et al. Science (1984) 226:1342; Gilligan et al. J. Med. Chem. (2000) 43:1641; Grigoriadis et al. Curr. Med. Chem.—CNS Agents (2001) 1:63; Owens et al. CNS Drugs (1999) 12:85; Keck et al. Peptides (2001) 22:835; Arzt et al. Trends Pharmacol. Sci. (2006) 27:531.
Administration of CRF directly to the brain elicits behavioral, physiological, and endocrine responses identical to those observed for an animal exposed to a stressful environment. Accordingly, clinical data suggests that CRF receptor antagonists may be useful in the treatment of the neuropsychiatric disorders manifesting hypersecretion of CRF, and, in particular, may represent novel antidepressant and/or anxiolytic drugs. The first CRF receptor antagonists were peptides. U.S. Pat. No. 4,605,642; Rivier et al., Science (1984) 224:889. While these peptides established that CRF receptor antagonists can attenuate the pharmacological responses to CRF, peptide CRF receptor antagonists suffer from the usual drawbacks of peptide therapeutics including lack of stability and limited oral activity. More recently, small molecule CRF receptor antagonists have been reported. Because of the physiological significance of CRF, biologically-active, small molecules having significant CRF receptor binding activity are thought to be useful in the treatment of endocrine, psychiatric and neurologic conditions or illnesses, including stress-related disorders in general.
In fact, CRF has been implicated in a variety of diseases to date, as indicated by the following publications. It was reported that elevated concentrations of CRF in the cerebrospinal fluid of patients with major depression compared with healthy individuals; CRF-mRNA levels in the hypothalamus of depressive patients are higher than that of healthy individuals; and CRF receptors in cerebral cortex are reduced in suicide victims; plasma ACTH increase is diminished with administration of CRF to depressive patients. Journal of Endocrinology (1999) 160:1. CRF levels in the cerebrospinal fluid of some anxiety patients with obsessive-compulsive disorder, posttraumatic stress disorder or Tourette's syndrome are higher than in that of healthy individuals. Journal of Endocrinology (1999) 160:1. Plasma ACTH increase is diminished with administration of CRF to panic disorder patients. Exp. Clin. Endcrinol. Diabetes (1997) 105:65. Anxiety behavior has been observed in experimental animals by intracerebral administration of CRF. In addition, anxiety behavior is observed more frequently in CRF overexpressing mice than in normal mice. Journal of Endocrinology (1999) 160:1. CRF levels in the locus coeruleus are reduced by administration of anxiolytics. Exp. Clin. Endocrinol. Diabetes (1997) 105:65. Also, α-helical CRF(9-41), a peptide CRF antagonist, exhibits an antianxiety action in animal models. Brain Res. (1990) 509:80; Regulatory Peptides (1987) 18:37; J. Neurosci. (1994) 14:2579. Abnormal behavior withdrawal from alcohol or addictive drugs such as cocaine are inhibited by α-helical CRF(9-41), a peptide CRF antagonist Psychopharmacology (1991) 103:227.
CRF inhibits sexual behavior in rats. Nature (1983) 305:232. CRF reduces sleep in rats and is thus implicated the involvement in sleep disorder. Pharmacol. Biochem. Behav. (1987) 26:699. α-helical CRF(9-41), a peptide CRF antagonist, suppresses brain damage or electroencephalogram disturbances due to brain ischemia or NMDA receptor activation. TIPS (1996) 17:166. CRF elicits electroencephalogram and induces convulsions. Brain Res. (1983) 278:332. Cerebrospinal CRF levels are elevated in schizophrenic patients compared with healthy individuals. Am. J. Psychiatry (1987) 144:873. CRF content in the cerebral cortex is reduced in Alzheimer's disease patients, Parkinson's disease patients and progressive supranuclear palsy patients. Neurology (1987) 37, 905. CRF is reduced in the ganglia in Huntington's disease Neurology (1987) 37:905; Brain Res. (1987) 437:355. In addition, CRF administration has been found to enhance learning and memory in rats. Exp. Clin. Endcrinol. Diabetes (1997) 105:65.
CRF content in cerebrospinal fluid are reduced in amyotrophic lateral sclerosis patients. Oversecretion of ACTH and adrenocorticosteroids are exhibited in mice overexpressing CRF, these mice display abnormalities similar to Cushing's syndrome, including muscular atrophy, alopecia, and infertility. Endocrinology (1992) 130:3378. Cerebrospinal CRF is elevated in anorexia nervosa patients compared with healthy individuals, and plasma ACTH increase is low with administration of CRF to anorexia nervosa patients; and CRF suppress feeding in experimental animals. TIPS (1996) 17:166. Moreover, α-helical CRF(9-41), a peptide CRF antagonist, improves stress-induced hypophagia in animal models. Brain Res. Bull. (1986) 17:285. CRF has suppressed body weight gain in hereditary obese animals; a link has been suggested between low CRF levels and obesity syndrome; and the anorexic action and the body weight loss action of serotonin reuptake inhibitors has been possibly mediated by CRF release TIPS (1996) 17:166.
CRF acts centrally or peripherally to weaken gastric contraction and reduce gastric emptying Annals of the New York Academy of Sciences (1993) 697:233. Furthermore, reduced gastric function induced by abdominal surgery is recovered by α-helical CRF(9-41), a peptide CRF antagonist Am. J. Physiol. (1992) 262:G616. CRF promotes secretion of bicarbonate ion in the stomach, thereby lowering gastric acid secretion and suppressing cold restraint stress ulcers. Am. J. Physiol. (1990) 258:G152. Also, administration of CRF increases ulcers in non-restraint stress animals. Life Sci. (1989) 45:907. CRF suppresses small intestinal transit and promotes large intestinal transit, and defecation is induced. In addition, α-helical CRF(9-41), a peptide CRF antagonist, has a inhibiting action against restraint stress-induced gastric acid secretion, reduced gastric emptying, reduced small intestinal transit and promoted large intestinal transit. Gastroenterology (1988) 95:1510. Psychological stress in healthy individuals increases anxiety or sensations of gas and abdominal pain during colonic distension and CRF lowers the discomfort threshold. Gastroenterol. (1995) 109:1772; Neurogastroenterol. Mot. (1996) 8:9. Irritable bowel syndrome patients experience excessive acceleration of colonic motility with CRF administration compared to healthy individuals Gut (1998) 42:845.
Administration of CRF increases blood pressure, heart rate and body temperature, while α-helical CRF(9-41), a peptide CRF antagonist, suppresses stress-induced increases in blood pressure, heart rate and body temperature. J. Physiol. (1993) 460:221. CRF production is increased locally in inflammation sites in experimental animals and in the synovial fluid of rheumatic arthritis patients TIPS (1996) 17:166. CRF provokes degranulation of mast cells and promotes vascular permeability Endocrinology (1998) 139:403. CRF is detected in autoimmune thyroiditis patients Am. J. Pathol. (1994) 145:1159. Administration of CRF to experimental autoimmune encephalomyelitis rats has notably suppressed progression of symptoms such as paralysis. J. Immunol. (1997) 158:5751. Urocortin (a CRF analogue) has increased growth hormone secretion in a pituitary adenoma culture system from an acromegalia patient. Endocri. J. (1997) 44:627. Furthermore, CRF simulates secretion of cytokines such as interleukin-1 and interleukin-2 by leukocytes. J. Neuroimmunol. (1989) 23:256; Neurosci. Lett. (1990) 120:151. CRF administration and stress both suppress T lymphocyte proliferation and natural killer cell activity. α-helical CRF(9-41), a peptide CRF antagonist, improves the reduced function of these immune cells caused by CRF administration or stress. Endocrinology (1991) 128:1329. Breathing is notably increased by administration of CRF. Eur. J. Pharmacol. (1990) 182:405. Finally, aggravated breathing and insomnia have been observed as a result of CRF administration to elderly patients under chronic artificial respiration Acta Endocrinol. Copenh (1992) 127:200.
Thus, there is a need in the art for CRF antagonists.